Synthesis of indanones via solid-supported [2+2+2] cyclotrimerization

Article abstract of DOI:10.1021/jo7013565

(Chemical Equation Presented) A new facile approach toward natural and unnatural indanones has been developed, featuring a solid-supported [2+2+2] cyclotrimerization as the key step. This strategy has been applied to the chemo- and regioselective assembly of indanone arrays and to the total synthesis of a recently isolated indanone marine natural product.

Full text of DOI:10.1021/jo7013565

tions on a solid support can solve these problems, and we
recently accomplished the first highly selective formation of
pyridines via this strategy.1 Here we are reporting a new
synthetic route to natural and unnatural indanones via regio-
and chemoselective solid-supported [2+2+2] cyclotrimerization
reactions. Previous indanone syntheses via cycloadditions either
involved completely intramolecular cyclotrimerization reac-
tions,4,7 cyclotrimerization of enones,8 or cyclotrimerization
reactions with low regioselectivity.9
Synthesis of Indanones via Solid-Supported
[2+2+2] Cyclotrimerization
Ramesh S. Senaiar, Jesse A. Teske, Douglas D. Young, and
Alexander Deiters*
Department of Chemistry, North Carolina State UniVersity,
Campus Box 8204, Raleigh, North Carolina 27695
alex_deiters@ncsu.edu
The indanone core structure is widely disseminated among
pharmacologically active substances with a wide range of
biological activities, hence efficient and selective approaches
to their synthesis are in demand.10 Additionally, hundreds of
indanone natural products are known,11,12 most importantly the
pterosins (Figure 1), including pterosin P (1), mukagolactone
(2), and monachosorin A (3).13
ReceiVed June 27, 2007
A new facile approach toward natural and unnatural in-
danones has been developed, featuring a solid-supported
[2+2+2] cyclotrimerization as the key step. This strategy
has been applied to the chemo- and regioselective assembly
of indanone arrays and to the total synthesis of a recently
isolated indanone marine natural product.
FIGURE 1. Selected indanone natural products 1-4.
These molecules, and related structures, display a variety of
biological activities including smooth muscle relaxant activity,14
inhibition of cyclooxygenase,15 and mast cell stabilization.16
Recently, the indanone natural product 4 has been isolated from
a marine cyanobacterium.17 This compound shows promising
biological activity as a regulator of tumor angiogenesis by
inhibiting human vascular endothelial growth factor production.
However, low in vivo activity observed after the initial screening
requires additional structural modifications for further improve-
ment,17 but no total synthesis of 4 has been reported to date.
Our synthetic route to indanones commences with the
cyclotrimerization precursor 5, which was rapidly assembled
Recently we initiated a program in developing solid-supported
[2+2+2] cyclotrimerization reactions and applying these reac-
tions to the synthesis of functional molecules.1,2 [2+2+2]
cyclotrimerization reactions are versatile tools in the assembly
of carbo- and heterocyclic structures,3 and they have been
previously employed as key steps in total syntheses.4-6 How-
ever, their application is often hampered by regio- and chemose-
lectivity problems leading to complex product mixtures. This
is especially pronounced in cases where triple bonds with greatly
different reactivity (e.g., due to different substitution patterns)
are employed.3 Conducting [2+2+2] cyclotrimerization reac-
(7) Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45, 6239.
(8) Mori, N.; Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1999, 121, 2722.
(9) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Nishiyama, H.; Itoh, K.
Org. Biomol. Chem. 2004, 2, 1287.
(1) Senaiar, R. S.; Young, D. D.; Deiters, A. Chem. Commun. 2006,
1313.
(2) Young, D. D.; Senaiar, R. S.; Deiters, A. Chem. Eur. J. 2006, 12,
5563.
(10) Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.;
Salvino, J. M. J. Comb. Chem. 2006, 8, 597.
(3) (a) Chopade, P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307. (b)
Schore, N. E. [2+2+2] Cycloadditions. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, UK, 1991; Vol. 5, 1129. (c) Varela, J. A.; Saa, C. Chem.
ReV. 2003, 103, 3787. (d) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503.
(e) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (f) Vollhardt, K.
P. C. Angew. Chem., Int. Ed. 1984, 23, 539. (g) Kotha, S.; Brahmachary,
E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741.
(11) Syrchina, A. I.; Semenov, A. A. Khim. Prir. Soedin. 1982, 3.
(12) Fugmann, B.; Lang-Fugmann, S.; Steglich, W.; Adam, G. Rompp
encyclopedia of natural products; Thieme: New York, 2000.
(13) Satake, T.; Murakami, T.; Yokote, N.; Saiki, Y.; Chen, C. M. Chem.
Pharm. Bull. 1985, 33, 4175. Saito, M.; Umeda, M.; Enomoto, M.;
Hatanaka, Y.; Natori, S. Experientia 1975, 31, 829.
(14) Sheridan, H.; Frankish, N.; Farrell, R. Eur. J. Med. Chem. 1999,
34, 953.
(4) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem.,
Int. Ed. 2004, 43, 1998.
(15) Li, C. S.; Black, W. C.; Chan, C. C.; Ford-Hutchinson, A. W.;
Gauthier, J. Y.; Gordon, R.; Guay, D.; Kargman, S.; Lau, C. K.; Mancini,
J.; Ouimet, N.; Roy, P.; Vickers, P.: Wong, E.; Young, R. N.; Zamboni,
R.; Prasit P. J. Med. Chem. 1995, 38, 4897.
(16) Frankish, N.; Farrell, R.; Sheridan, H. J. Pharm. Pharmacol. 2004,
56, 1423.
(5) (a) Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1982, 47,
3447. (b) Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105,
6991. (c) Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.;
Schmidt, M.; Vollhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324.
(6) Witulski, B.; Zimmermann, A.; Gowans, N. D. Chem. Commun. 2002,
2984.
(17) Nagle, D. G.; Zhou, Y. D.; Park, P. U.; Paul, V. J.; Rajbhandari, I.;
Duncan, C. J. G.; Pasco, D. S. J. Nat. Prod. 2000, 63, 1431.
10.1021/jo7013565 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/07/2007
J. Org. Chem. 2007, 72, 7801-7804
7801

SCHEME 1. (a) Synthesis of Immobilized
Cyclotrimerization Precursors 5-7 and (b) Alkyne Reaction
Partners 11-19
SCHEME 2. Solid-Supported Formation of Indanones
21-29
in only 2 steps.18 On the basis of our previous results with
[2+2+2] cyclotrimerization reactions, conducting the reaction
via spatial separation of diyne starting materials on a solid
support alleviates chemoselectivity issues prevalent in solution
such as the di- and trimerization of starting materials.1,2,19,20
Performing these reactions on a solid support, especially with
a low loading of 0.2 mmol g-1, prevents these side reactions
despite the flexibility of the employed TentaGel resin (NovaSyn
TG, NovaBiochem, loading 0.25 mmol/g). This affords signifi-
cantly higher yields and products of higher purity (especially
in the case of less reactive internal monoalkynes). A high level
of synthetic flexibility was achieved by employing an im-
mobilization strategy in which the position of linkage to the
solid phase is not visible in the final product.21
SCHEME 3. Regioselective Solid-Supported [2+2+2]
Cyclotrimerization toward Indanones
Due to the acid-sensitive nature of the benzylic C-O bond
in the indanol cyclotrimerization products, the alcohol 5 was
immobilized via a carboxy linker that can be cleaved under mild
basic conditions. Initial experiments with an acid-cleavable
Wang or trityl linker did not deliver any product. The im-
mobilized 8 was assembled by reacting the resin with 5 (5 equiv)
in the presence of DCC in DCM, and a loading of 0.2 mmol
g-1 was obtained (as determined by GC/MS analysis). The
excess of diyne 5 could be fully recovered.
The first cyclotrimerization attempts with 8 by using the
classical Wilkinson’s catalyst (RhCl(Ph3P)3)19,22 led to incon-
clusive results and cleavage of the diyne from the resin, although
propargyl acetates have previously been employed in Rh-
catalyzed cyclotrimerizations.6,19,23 The [2+2+2] cyclotrimer-
ization proceeded smoothly at room temperature when Cp*Ru-
(COD)Cl was used as a catalyst.20 A set of nine alkynes (11-
19, Scheme 1) was investigated, revealing that the reaction was
compatible with a variety of functionalities, including alkyl
chains (in 12), aromatic rings (in 13 and 17), alkoxy groups (in
16, 17, and 19), carbamates (in 18), halides (in 14), and cyano
groups (in 15). The cyclotrimerized products were released from
the resin by treatment with K2CO3 in MeOH/THF. A subsequent
solvent change to CH2Cl2 followed by oxidation with PDC
delivered the indanones 21-29 in good yields (58-78% over
three steps) and with excellent purity (>90% by 1H NMR and
GC/MS analysis). Alternative oxidizing agents (e.g., MnO2 and
Dess-Martin’s periodinane) delivered indanones in slightly
lower yields.
Since the reaction mechanism does not allow differentiation
between the two triple bonds in the precursor 8, mixtures of
two regioisomers are observed. The regioisomeric ratio, as
determined by 1H NMR, ranges from 1:2 to 2:3, with a minimal
preference for the formation of the regioisomers 22b-28b. The
regioisomeric ratio shown for 22-28 was determined based on
the integration of the signal for the aromatic proton at C-7, which
occurs farthest downfield in the NMR spectrum. In the case of
regioisomers 22a-28a the signal for the proton at C-7 is a
singlet, while in the opposite regioisomers 22b-28b this signal
occurs as a doublet. This regioisomer assignment was later
confirmed by the regioselective preparation of 22b-26b (see
Scheme 3).
(18) Kim, D. H.; Son, S. U.; Chung, Y. K.; Lee, S. G. Chem. Commun.
2002, 56.
(19) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1
1988, 1357.
(20) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem.
Soc. 2003, 125, 12143.
(21) (a) Delgado, M.; Janda, K. D. Curr. Org. Chem. 2002, 6, 1031. (b)
Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091.
(22) Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988, 44, 4967.
(23) Witulski, B.; Zimmermann, A. Synlett 2002, 1855.
7802 J. Org. Chem., Vol. 72, No. 20, 2007

SCHEME 4. Regioselective Solid-Supported [2+2+2]
To demonstrate the enhancing effect of the solid support, a
solution-phase three-step transformation of O-acetylated 5 to
22 under conditions resembling the solid-phase reaction (20 mM
substrate, 10 equiv of 1-hexyne) was conducted. This led to a
diminished overall yield of 28% (the solution-phase cyclotri-
merization step alone only showed a 37% yield, 1:2 regiose-
lectivity) for 22. This lower yield is a result of competing side
reactions in the [2+2+2] cyclotrimerization step (as discussed
earlier), which are not observed on the solid support. Previously,
the di- and trimerization of diyne starting materials has been
addressed in a less general fashion through the usage of internal
diynes or the application of high-dilution conditions in conjunc-
tion with a slow diyne addition over an extended period of time.3
Even though the formation of two regioisomers increases the
structural diversity in generated indanone arrays, a selective
cyclotrimerization leading to only one product is highly desir-
able. To impose regioselectivity on the solid-supported cyclo-
trimerization, the precursor 9 was synthesized bearing a
removable regiodirecting group (TMS).4 Due to the steric bulk
of the TMS group, the meta isomer 30 is expected to be the
major product (Scheme 3). Cyclotrimerization reactions were
carried out with terminal alkynes under standard conditions,
followed by cleavage and oxidation.20 Investigations into
removal of the TMS group were conducted on both the reduced
and oxidized indanone. Traditional conditions (TFA, HBr,
TBAF, and NH4F) all yielded little to no desilylation at room
temperature or at elevated temperature.24 The TMS group was
ultimately removed by treatment with TBAF in 4:1 THF/DMF
under microwave irradiation, delivering the indanones 22b-
26b in good yields (57-74% over the complete 4-step proce-
dure) and as single regioisomers.
Cyclotrimerization toward Methyl-Substituted Indanones
SCHEME 5. Solid-Supported Synthesis of the Indanone
Natural Product 4
The regioisomer shown for 22b-26b was assigned based on
the 1H NMR spectrum, which displays a doublet for the
downfield shifted proton H-7 due to its coupling to H-6. The
1H NMR spectra of the products correspond to a single
regioisomer when compared to the mixtures previously obtained
(see Scheme 2). On the basis of the integration of the NMR
signal for H-5 the regioisomeric ratio was determined to >95:
5. Overall, the [2+2+2] cyclotrimerization reactions of the
sterically more hindered 9 lead to comparable product yields
to the non-silylated substrate 8, while delivering pure regioi-
somers.
and C-4. In the case of the opposite regioisomer, doublets for
those protons would be expected. On the basis of these
assignments in the NMR spectrum the regioisomeric ratio was
determined to >95:5.
These results set the stage for the synthesis of indanone
natural products via solid-supported [2+2+2] cyclotrimeriza-
tions. We selected the marine natural product 4, which was
recently isolated from the filamentous marine cyanobacterium
Lyngbya majuscula,17 as a target molecule since no total
synthesis has been reported to date. Moreover, it exhibits
promising antiangiogenesis activity,17 which could potentially
be improved through the availability of a facile synthetic
approach to analogues. The immobilized cyclotrimerization
precursor 39 was assembled in 7 steps from known material
(see the Supporting Information). Again, a carboxy linkage to
the polymeric support was chosen due to the acid lability of
the indanol (as discussed above). Since the natural product was
reported to be nearly racemic no attempt to generate enantio-
merically pure 39 was undertaken. The precursor 39 was
cyclotrimerized with propyne to furnish immobilized 40 under
the conditions established in previous experiments. After
treatment of 40 with K2CO3 in THF/MeOH the resulting indanol
was oxidized with solid-supported IBX (2-iodoxybenzoic acid
polystyrene, Novagen), conveniently leading to an unexpected
acetal cleavage by the solid-supported oxidizing agent. The
natural product 4 was obtained in excellent yield (72% over
These studies demonstrate the applicability of solid-supported
cyclotrimerizations to the chemo- and regioselective formation
of natural and unnatural indanones. Since several indanone
natural products display a methyl group in the 7-position,11 the
cyclotrimerization precursor 10 was assembled (following a
previously employed protocol18). Although a highly regiose-
lective [2+2+2] cyclotrimerization as in the case of 9 was
expected, the regioselectivity inducing effect of a sterically
smaller methyl group (compared to a TMS group) needed to
be investigated. The reaction of 10 with terminal alkynes via
the standard cyclotrimerization protocol smoothly led to the
formation of 31 (Scheme 4), followed by the cleavage-
oxidation sequence yielding the methyl indanones 32-38 as
the only regioisomers. Yields for the three-step process ranged
from 63% to 74% and purities were observed to be >90%. The
regioisomer shown for 33-38 was assigned based on singlets
1
in the H NMR spectrum for the aromatic protons at both C-6
(24) (a) Toyota, M.; Terashima, S. Tetrahedron Lett. 1989, 30, 829. (b)
Aalbersberg, W. G. L.; Barkovich, A. J.; Funk, R. L.; Hillard, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1975, 97, 5600.
J. Org. Chem, Vol. 72, No. 20, 2007 7803

General Cyclotrimerization Procedure. Diyne derivatized resin
(50 mg, 0.05 mmol) was placed into a flame-dried vial and was
suspended in dichloroethane (2 mL) under a nitrogen atmosphere.
The soluble alkyne (0.50 mmol) was added and the solution was
degassed with 3 freeze-pump-thaw cycles. The Cp*Ru(COD)Cl
catalyst (2 mg, 0.01 mmol) was added and the reaction was shaken
at room temperature for 24 h. The resin was then transferred to a
syringe filter, washed with alternating rinses of DCM and MeOH
(4 × 3 mL), and subsequently dried under vacuum.
three steps) and as the only regioisomer. All spectroscopic data
are in agreement with the literature.17
In contrast, solution-phase [2+2+2] cyclotrimerization reac-
tions toward 4 were much less successful. A trityl protected
precursor of 39 (see the Supporting Information) failed to
undergo cyclotrimerization, most likely due to strong sterical
interactions in the aromatic product between the trityl group
on O-1 and the diethylacetal. The solution-phase [2+2+2]
cyclotrimerization of an O-1 acetylated precursor (not shown),
resembling the carboxy linker in 39, provided the cyclotrimer-
ization product in only 56% yield. This yield is considerably
lower than the 72% yield in the case of the solid-phase reaction
shown in Scheme 5, which also includes the subsequent
deprotection and oxidation. Thus, the solid-phase cyclotrimer-
ization approach enables the facile synthesis of analogues of 4
to further improve its antiangiogenesis activity.
In summary, an efficient and facile approach to natural and
unnatural indanones via a solid-supported [2+2+2] cyclotrim-
erization has been accomplished. An immobilization strategy
was realized that does not show any remains of the linkage site
to the solid support in the final product. Chemo- and regiose-
lectivity issues typically observed in cyclotrimerization reactions
have been resolved, and arrays of differently substituted
indanones have been constructed. The applicability of the
developed approach to total synthesis has been demonstrated
through the assembly of a marine natural product. The biological
activities of the synthesized compounds, especially of 4 and
analogues thereof, will be investigated in due course.
General Cleavage and Oxidation Procedure. Dried resin
carrying the cyclotrimerized product was transferred to a vial, THF
and MeOH (4:1, 500 µL) were added followed by K2CO3 (20 mg,
0.14 mmol), and the suspension was shaken for 16 h at room
temperature. The filtrate was removed, concentrated, and dissolved
in DCM (1 mL). PCC (15 mg, 0.07 mmol) or PDC (26 mg, 0.07
mmol) was added and the solution was stirred overnight at room
temperature. The reaction mixture was filtered through a silica plug
followed by a rinse with DCM (2 mL), and concentrated to yield
pure indanone products. All yields were determined by measuring
the mass balance of pure indanones and correlating the amount of
material to the loading of the resin.
General Desilylation Procedure. Oxidized TMS-indanones
were dissolved in THF (400 µL), transferred to a microwave vial,
and treated with DMF (100 µL) followed by 1.0 M TBAF in THF
(50 µL, 0.05 mmol), and the reaction was placed in a CEM Discover
Microwave Synthesizer for 2 min (300 W, ∼200 °C). The reaction
was then passed through a silica plug that was subsequently rinsed
with hexanes (2 mL), and the filtrate was concentrated to yield
pure desilylated indanone products. Overall indanone yields ranged
from 57% to 78% and products were obtained in quantities of 2.6-
7.2 mg.
Experimental Section
Acknowledgment. We gratefully acknowledge support by
the Department of Education (GAANN Fellowship for D.D.Y),
the NCSU Faculty Research and Development Fund, and the
Donors of the American Chemical Society Petroleum Research
Fund for partial support of this research.
General Diyne Immobilization Procedure. Carboxylic acid
derivatized resin (1.0 g, 1.2 mmol) was allowed to swell for 15
min in DCM (6 mL). The diyne (6 mmol) was added, followed by
DMAP (29 mg, 0.24 mmol) and dicyclohexylcarbodiimide (0.93
mL, 6 mmol), and the reaction was shaken at room temperature
for 12 h. The resin was transferred to a syringe filter and washed
with alternating rinses of DCM and MeOH (4 × 5 mL). The resin
was dried under vacuum and an aliquot of 15 mg was cleaved (25
mg of K2CO3, 500 µL 4:1 THF/MeOH, 12 h). The loading was
determined via GC/MS analysis by generating a standard curve of
the diyne starting material within the range of expected loading
(100, 50, and 25 mM).
Supporting Information Available: Analytical data of in-
1
danones 21-38, synthesis of 4 and 39, and H NMR spectra of
compounds 4, 21-29, and 32-38. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO7013565
7804 J. Org. Chem., Vol. 72, No. 20, 2007